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* Surgery Branch,
Laboratory of Molecular Biology, and
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
CD25+CD4+ T regulatory (Treg) cells regulate peripheral self tolerance and possess the ability to suppress antitumor responses, which may in part explain the poor clinical response of cancer patients undergoing active immunization protocols. We have previously shown that in vitro incubation of human PBMC with LMB-2, a CD25-directed immunotoxin, significantly reduced CD25+FOXP3+CD4+ Treg cells without impairing the function of the remaining lymphocytes. In the current study, eight patients with metastatic melanoma were treated with LMB-2 followed by MART-1 and gp100-specific peptide vaccination. LMB-2 administration resulted in a preferential, transient reduction in mean circulating CD25+CD4+ T cell number, from 83 ± 16 cells/µl to a nadir of 17 ± 5 cells/µl, a 79.1% reduction. FOXP3 analysis revealed a less robust depletion with mean FOXP3+CD4+ Treg cell number decreasing from 74 ± 15 cells/µl to 36 ± 8 cells/µl, a 51.4% reduction. FOXP3+CD4+ Treg cells that survived LMB-2-mediated cytotoxicity expressed little or no CD25. Similar to the peripheral blood, immunohistochemical analysis showed a 68.9% mean reduction in FOXP3+CD4+ Treg cell frequency in evaluable lesions. Despite inducing a reduction in Treg cell numbers in vivo, LMB-2 therapy did not augment the immune response to cancer vaccination and no patient experienced an objective response or autoimmunity. These data demonstrate the capacity of a CD25-directed immunotoxin to selectively mediate a transient partial reduction in circulating and tumor-infiltrating Treg cells in vivo, and suggest that more comprehensive Treg cell elimination may be required to bolster antitumor responses in patients with metastatic melanoma.
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1 This work was supported (in part) by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.
2 Address correspondence and reprint requests to Dr. Daniel J. Powell, Jr., Surgery Branch, Clinical Research Center, National Cancer Institute, National Institutes of Health, Room 3W-3888, 10 Center Drive, MSC 1201, Bethesda, MD 20892-1201. E-mail address: Daniel_Powell{at}nih.gov
3 Abbreviations used in this paper: Treg, T regulatory; ALC, absolute lymphocyte count; TIL, tumor-infiltrating T cell; IHC, immunohistochemical; GVHD, graft-vs-host disease; QOD, every other day.
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